Cancer is one of the leading causes of death and disability in the United States. Each year, over 1 million new cases of cancer are diagnosed. Despite the seriousness of the disease, many people survive cancer, with the chances of success often being directly related to whether the cancer is detected at an early stage. For decades researchers have attempted to identify and understand physiological events associated with cancer. Through an improved understanding of cancer and its causes it may be possible to identify better methods for detection, prevention, and treatment.
Cancer can attack almost any portion of the body and often has far-reaching effects within the body of an afflicted individual. When a patient gets cancer many systems in the body undergo changes. These changes may be due to organ failure as the tumor grows to take over the organ(s). Other changes may be due to the increased metabolic rate of the tumor, cell death in or around the tumor, or even due to compounds secreted by the tumor. These various changes in response to tumor growth are known as the pathophysiology of cancer.
Specific examples of physiological changes associated with cancer include the visually devastating retina degenerations, cancer associated retinopathy (CAR) and melanoma associated retinopathy (MAR). Fortunately these severe retinopathies are quite rare (estimated one/100,000 cancer patients). As their names imply, these pathologies are associated with the retina. The retina is the portion of the visual system at the back of the eye responsible for collecting the visual stimuli (light). The light is then converted into impulses decoded by the brain and perceived as vision. The retina is composed of many cell types, with each cell type having a specific function. Cells in the retina are responsible for light detection, signal processing, signal transmission, structural and nutritive functions. The light detection portion is composed of cells known as photoreceptors. Two photoreceptor cell types are present in the primate retina, rods and cones. The rods are responsible for our ability to detect low levels of light, such as the ability to see at night. Among the cones are three types, red, green, and blue. These three types of cones are responsible for the color vision experienced by humans. Fine visual acuity that is present in primates (humans included) occurs due to the cellular composition of a region of the retina, called the macula. Light detection and the ability to see details occur in the macula and are due to cone function. Macular vision uses predominantly cones of the red and green types.
Each type of cone cell contains a different set of light activated pigment proteins. Each pigment type responds to light of a different color. The cone cells also have other biochemical and protein features that make each cone type unique. In the blue cones, one protein is of particular interestxe2x80x94Carbonic Anhydrase (CA).
Rare but serious visual losses have been reported which occur as paraneoplastic retinopathies associated with carcinoma of the lung (Jordan, B. L., W. W. Dawson, T. Fang [1998] Invest Opthalmol Vis Sci. 39:s402) and less often with cervix, colon, prostate and breast cancers (Dawson, W., B. Jordan, K. Hazariwala, T. Fang, R. Marsh, presented in Prague, Czech Republic at annual ISCEV meeting, spring 1998). Cancer associated retinopathy (CAR) is characterized by rapid onset, progressive acuity loss and mild-to-moderate fundus changes. A related and even more rare retinopathy has been associated with malignant melanoma of the skin (MAR) (Posner, J. B., J. Dalmau [1995] Clin Neurol Neurosurg. 97:61-70; Alarcon-Segovia, D., A. Ruiz-Arguelles, L. Llorente [1996] Immunology Today 17:163-164). MAR is typified by sudden onset of night xe2x80x9cblindnessxe2x80x9d, bizarre visual image alterations and xe2x80x9cmovingxe2x80x9d lights. Circulating factors and autoimmune responses at various retinal sites have been implicated in both diseases (Darnell, R. B. [1996] Proc. Natl. Acad. Sci USA 93:45294536; Korngruth, S. E. [1989] N Eng J Med 321, 23:1607-1608). Patients seldom seek speciality eye care before there is a significant change in central vision, such as in CAR or MAR.
Although a growing number of anticancer agents have been identified, the treatment of cancer is still fraught with difficulties and uncertainties. Effective detection and treatment of cancer is particularly challenging because of the many different types of cancer and the associated complexities involved in accurately identifying the presence of a particular form of cancer, and then identifying and applying the proper treatment regimen.
In recent years, a growing number of diagnostic methods have been devised for identifying the presence of cancer. Many of these diagnostic methods are based upon immunological characteristics such as antigen and/or antibody recognition procedures. These procedures are often labor intensive, difficult to interpret or quantify, require a blood sample, and are so specific that only certain forms of cancer are detected. Therefore, a need exists for new methods for identifying those at risk for cancer and/or those in the early stages of cancer. Also, accurate and simple methods for monitoring the progression of cancer are needed.
The subject invention concerns the identification of retinal dysfunctions associated with neoplastic disease. The retinal dysfunctions are observed in patients who have undergone treatment for cancer as well as those who have not undergone treatment. Thus, according to the subject invention it has been determined that physiological responses associated with cancer are manifested as early detectable changes in the retina. In a preferred embodiment, the subject invention pertains to non-invasive tests whereby the existence of certain retinal dysfunctions indicate the presence and/or status of neoplastic disease.
The diagnostic methods of the subject invention involve the identification of an acquired retinal dysfunction in individuals with cancer. The retinal dysfunctions which are the basis of the diagnostic test of the subject invention can be detected as described herein despite the fact that best corrected visual acuity is seldom reduced or abnormal. The methods of the subject invention can be used to identify patients having any of a variety of cancers including, but not limited to, breast, colon, lung, skin, and testicular cancer. Retinal deficits have been found in patients prior to chemotherapy and, advantageously, the test of the subject invention facilitates very early diagnosis of cancer.
The clinical condition detected according to the methods described herein has been termed Cancer Associated Retinal Deficit (CARD). CARD is very different from, and should not be confused with, cancer and melanoma associated retinopathy (CAR and MAR, respectively). CARD does not involve the common clinically detected causes of visual loss (cataracts, glaucoma, macular degeneration, etc.). Also, the functional changes in CARD patients do not appear to be due to chemotherapy, since there is no visible ophthalmologic retinal damage, it exists prior to chemotherapy, and is present in many patients who have received different treatment regimens.
In a particularly preferred embodiment, the presence of cancer is identified based on dysfunctions in color vision, dark adaptation, ERG, and/or EEG. These results can be augmented with results from, for example, a dilated eye examination which can rule out other sources of vision dysfunction.
Results of tests utilizing the methods of the subject invention indicate that a very high proportion of cancer patients have CARD. The majority of these changes are proving to be undetectable in a routine clinical eye exam.
Prior to the current invention, individuals with CARD syndrome were often dismissed (by the ophthalmologist and/or other physician) and told that the vision problems are functional or age related. Proper identification of CARD according to the subject invention is an important diagnostic procedure which can be used to improve quality of patient life and improve cancer survival statistics.